Dataset Information

Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation.

ABSTRACT: Mycophenolate-related anemia and leukopenia are well-known toxicities after transplantation. Toxicity leads to dose reduction, addition of colony-stimulating factors or erythropoietin, or discontinuation of immunosuppressive therapy. The causes of and risk factors associated with toxicity are unclear.We studied the association between mycophenolate-related anemia and leukopenia and 2724 single nucleotide polymorphisms (SNP) in 978 patients undergoing living or deceased donor kidney transplant. Patients were followed up to time of first anemia (hemoglobin<10 gm/dL or hematocrit<30%) or first leukopenia (white blood cell [WBC] count <3000 cells/mm), which required clinical intervention in the first 6 months after transplant.Anemia occurred in 87 (9.5%) subjects and leukopenia in 224 (22.9%). In single SNP analyses, none of the SNPs were associated with time to leukopenia at a false discovery rate (FDR) of 20%. However, SNPs from the IL12A, HUS, CYP2C8 genes were associated with time to anemia, allowing for an FDR of 20%. To assess the independence of these SNPs as predictors of anemia, we conducted a multi-SNP analysis including one SNP from each of the three genes. All three SNPs were associated with time to anemia, after adjusting for recipient age, weight, posttransplant dialysis and antiviral drug use, and stratifying by clinical center.Although these SNPs require validation in an independent population, our results suggest that genetics may play a role in risk of mycophenolate-related hematologic toxicity. This may ultimately provide for better management of maintenance immunosuppression and gives insights into potential mechanism(s) by which toxicity occurs.

SUBMITTER: Jacobson PA

PROVIDER: S-EPMC3711617 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation.

Jacobson Pamala A PA Schladt David D Oetting William S WS Leduc Robert R Guan Weihau W Matas Arthur J AJ Lamba Vishal V Mannon Roslyn B RB Julian Bruce A BA Israni Ajay A

Transplantation 20110201 3

<h4>Background</h4>Mycophenolate-related anemia and leukopenia are well-known toxicities after transplantation. Toxicity leads to dose reduction, addition of colony-stimulating factors or erythropoietin, or discontinuation of immunosuppressive therapy. The causes of and risk factors associated with toxicity are unclear.<h4>Methods</h4>We studied the association between mycophenolate-related anemia and leukopenia and 2724 single nucleotide polymorphisms (SNP) in 978 patients undergoing living or ...[more]

PMID: 21107304

Similar Datasets

Project description:Hypercholesterolemia, also called high cholesterol, is a form of hyperlipidemia, which may be a consequence of diet, obesity or diabetes. In addition, increased levels of low-density lipoprotein (LDL) and reduced levels of high-density lipoprotein (HDL) cholesterol are associated with a higher risk of atherosclerosis and coronary heart disease. Thus, controlling cholesterol levels is commonly necessary, and fibrates have been used as lipid-lowering drugs. Gemfibrozil is a fibrate that acts via peroxisome proliferator-activated receptor alpha to promote changes in lipid metabolism and decrease serum triglyceride levels. However, anemia and leukopenia are known side effects of gemfibrozil. Considering that gemfibrozil may lead to anemia and that gemfibrozil acts via peroxisome proliferator-activated receptor alpha, we treated wild-type and peroxisome proliferator-activated receptor alpha-knockout mice with gemfibrozil for four consecutive days. Gemfibrozil treatment led to anemia seven days after the first administration of the drug; we found reduced levels of hemoglobin, as well as red blood cells, white blood cells and a reduced percentage of hematocrits. PPAR-alpha-knockout mice were capable of reversing all of those reduced parameters induced by gemfibrozil treatment. Erythropoietin levels were increased in the serum of gemfibrozil-treated animals, and we also observed an increased expression of hypoxia-inducible factor-2 alpha (HIF-2α) and erythropoietin in renal tissue, while PPAR-alpha knockout mice treated with gemfibrozil did not present increased levels of serum erythropoietin or tissue HIF-2α and erythropoietin mRNA levels in the kidneys. We analyzed bone marrow and found that gemfibrozil reduced erythrocytes and hematopoietic stem cells in wild-type mice but not in PPAR-alpha-knockout mice, while increased colony-forming units were observed only in wild-type mice treated with gemfibrozil. Here, we show for the first time that gemfibrozil treatment leads to anemia and leukopenia via peroxisome proliferator-activated receptor alpha in mice.

Project description:As obesity, circulating lipids and other vascular/metabolic factors influence the risk of stroke, we examined if genetic variants associated with these conditions are related to risk of stroke using a case-control study in Galicia, Spain. A selection of 200 single-nucleotide polymorphisms previously found to be related to obesity, body mass index, circulating lipids, type 2 diabetes, heart failure, obesity-related cancer and cerebral infarction were genotyped in 465 patients diagnosed with stroke and 480 population-based controls. An unsupervised Lasso regression procedure was carried out for single-nucleotide polymorphism selection based on their potential effect on stroke according to obesity. Selected genotypes were further analysed through multivariate logistic regression to study their association with risk of stroke. Using unsupervised selection procedures, nine single-nucleotide polymorphisms were found to be related to risk of stroke overall and after stratification by obesity. From these, rs10761731, rs2479409 and rs6511720 in obese subjects [odds ratio (95% confidence interval) = 0.61 (0.39-0.95) (P = 0.027); 0.54 (0.35-0.84) (P = 0.006) and 0.42 (0.22-0.80) (P = 0.0075), respectively], and rs865686 in non-obese subjects [odds ratio (95% confidence interval) = 0.67 (0.48-0.94) (P = 0.019)], were independently associated with risk of stroke after multivariate logistic regression procedures. The associations between the three single-nucleotide polymorphisms found to be associated with stroke risk in obese subjects were more pronounced among females; for rs10761731, odds ratios among obese males and females were 1.07 (0.58-1.97) (P = 0.84), and 0.31 (0.14-0.69) (P = 0.0018), respectively; for rs2479409, odd ratios were 0.66 (0.34-1.27) (P = 0.21), and 0.49 (0.24-0.99) (P = 0.04), for obese males and females, respectively; the stroke-rs6511720 association was also slightly more pronounced among obese females, odds ratios were 0.33 (0.13-0.87) (P = 0.022), and 0.28 (0.09-0.85) (P = 0.02) for obese males and females, respectively. The rs865686-stroke association was more pronounced among non-obese males [odds ratios = 0.61 (0.39-0.96) (P = 0.029) and 0.72 (0.42-1.22) (P = 0.21), for non-obese males and females, respectively]. A combined genetic score of variants rs10761731, rs2479409 and rs6511720 was highly predictive of stroke risk among obese subjects (P = 2.04 × 10-5), particularly among females (P = 4.28 × 10-6). In summary, single-nucleotide polymorphisms rs1076173, rs2479409 and rs6511720 were found to independently increase the risk of stroke in obese subjects after adjustment for established risk factors. A combined score with the three genomic variants was an independent predictor of risk of stroke among obese subjects in our population.

Project description:Cardiomyopathy has been recognized as a complication after hematopoietic cell transplantation (HCT). Using a nested case-cohort design, we examined the relationships between demographic, therapeutic, and selected cardiovascular disease risk factors among ≥1-year HCT survivors who developed cardiomyopathy before (n = 43) or after (n = 89) 1 year from HCT as compared to a randomly selected subcohort of survivors without cardiomyopathy (n = 444). Genomic data were available for 79 cases and 267 noncases. Clinical and genetic covariates were examined for association with the risk of early or late cardiomyopathy. Clinical risk factors associated with both early- and late-onset cardiomyopathy included anthracycline exposure ≥250 mg/m(2) and pre-existing hypertension. Among late-onset cardiomyopathy cases, the development of diabetes and ischemic heart disease further increased risk. We replicated several previously reported genetic associations among early-onset cardiomyopathy cases, including rs1786814 in CELF4, rs2232228 in HAS3, and rs17863783 in UGT1A6. None of these markers were associated with risk of late-onset cardiomyopathy. A combination of demographic, treatment, and clinical covariates predicted early-onset cardiomyopathy with reasonable accuracy (area under the curve [AUC], .76; 95% confidence interval [CI], .68 to .83), but prediction of late cardiomyopathy was poor (AUC, .59; 95% CI .53 to .67). The addition of genetic polymorphisms with marginal associations (odds ratios ≥1.3) did not enhance prediction for either early- or late-onset cardiomyopathy. Conventional cardiovascular risk factors influence the risk of both early- and late-onset cardiomyopathy in HCT survivors. Although certain genetic markers may influence the risk of early-onset disease, further work is required to validate previously reported findings and to determine how genetic information should be incorporated into clinically useful risk prediction models.

Dataset Information

Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation.

Publications

Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure